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1
2, Fas Ligand, and TNF-Related Apoptosis-Inducing Ligand1
,¶,
*
University of Pittsburgh Cancer Institute and Departments of
Pathology,
Otolaryngology, and
Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15231; and
¶ Institute for Oncology and Radiology, Belgrade, Yugoslavia
research fellow supported by 1-PO DE13059-01 National Institutes of Health Oral Cancer Center Grant.
Our recent studies have demonstrated that human immature dendritic
cells (DCs) are able to directly and effectively mediate apoptotic
killing against a wide array of cultured and freshly-isolated cancer
cells without harming normal cells. In the present study, we
demonstrate that this tumoricidal activity is mediated by multiple
cytotoxic TNF family ligands. We determine that human immature DCs
express on their cell surface four different cytotoxic TNF family
ligands: TNF, lymphotoxin-
1
2, Fas ligand,
and TNF-related apoptosis inducing ligand; while cancer cells express
the corresponding death receptors. Disruptions of interactions between
the four ligands expressed on DCs and corresponding death-signaling
receptors expressed on cancer cells using specific Abs or R:Fc fusion
proteins block the cytotoxic activity of DCs directed against cancer
cells. The novel findings suggest that DC killing of cancer cells is
mediated by the concerted engagement of four TNF family ligands of DCs
with corresponding death receptors of cancer cells. Overall, our data
demonstrate that DCs are fully equipped for an efficient direct
apoptotic killing of cancer cells and suggest that this mechanism may
play a critical role in both afferent and efferent anti-tumor
immunity.
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